The field of the invention is vaccines for preventing or reducing the severity of infectious diseases. More particularly, the invention is concerned with vaccines against pathogenic microorganisms which resist neutrophil destruction by inhibiting degranulation.
The mechanisms by which bacteria resist phagocytic destruction have been summarized by Densen and Mandel: "Reviews of Infectious Diseases," Vol. 2, No. 5, Sept.-Oct. 1980, pages 817-838. Relevant here is the phagocytosis sequence in which polymorphonuclear neutrophils (PMNs) ingest invading bacteria and the PMNs granules move toward and merge with the phagosome containing the ingested microorganisms, releasing enzymes which assist in the destruction of the bacteria. If degranulation is inhibited or does not occur at all, ingested microorganisms may be able to survive within the PMNs. In Table 1 (page 821), Densen and Mandel list some pathogens which have been reported to inhibit degranulation, including Mycobacteria.sup.1 species M. tuberculosis, M. microti, and M. bovis. and also Toxoplasma gondii. It appears, however, that prior reports have related to fixed macrophages in the tissues rather than circulating PMNs.
Prior to the experimental work leading to the present invention, the mechanisms by which certain microorganisms inhibit degranulation of PMNs is not known to have been elucidated. In macrophages, cyclic AMP (cAMP), a well-known cell regulator, was reported to play a role in the inhibition of macrophage degranulation by Mycobacteria. See Lowrie et al. (1975), Nature, 254:600-602; and Lowrie et al. (1979), J. Gen. Microbiol., 110:431-441. These researchers found that macrophages ingesting live mycobacteria had increased concentrations of intracellular cyclic AMP. It was suggested that at least part of the cAMP may have been produced by the bacteria but this speculation was not confirmed. Cyclic AMP as well as cyclic GMP (cGMP) are known to be important intracellular regulatory molecules. In general, increased intracellular cAMP tends to inhibit cell functions while increased cGMP enhances cell functions.
The regulation of macrophage lysosomal secretion by adenosine and related compounds has recently been reported: Riches, et al. (1985), J. Leukocyte Biol., 37:545-557. Riches et al. found that zymosan particle-stimulated beta-galactosidase secretion by mouse peritoneal macrophages could be inhibited by adenosine, AMP, and related compounds, as well as guanosine.